CONTEXT: Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression....CONCLUSIONS: The magnitude of benefit of antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.

So what’s the bottom line? In clinical practice, many people suffering from depression improve after taking antidepressants. But the evidence indicates that much of that improvement is a placebo response. Antidepressants do work in the sense that many patients in clinical practice show substantial improvement. However, if the standard is efficacy in comparison to placebo, the best available scientific evidence suggests that antidepressants do not work very well. Given their cost and side effects, the psychiatric community and the general public should not be satisfied with antidepressant medications that provide only a marginal benefit over placebo.

Excerpt from highly reputable and widely respected David D. Burns’ (M.D.) book When Panic Attacks: The New, Drug-Free Anxiety Therapy That Can Change Your Life

Why is the placebo effect so important? Our expectations can have powerful influences on the way we think, feel, and behave. If you’re convinced that something will help, there’s a good chance that it will help, even if it has no real effects at all. Let’s say that you and I work as marketing executives for a pharmaceutical company. One day, at a press conference, we announce the synthesis of a wonderful new antidepressant called Placebin. We emphasize the superior antidepressant effects of the new drug and explain that it has few or no side effects and virtually no toxic effects. In fact, we’re so excited by this new breakthrough drug that we’re going to give Placebin to a million depressed people absolutely free of charge in a huge, nationwide clinical trial. There’s tremendous enthusiasm for Placebin, and our company’s stock goes up by more than $1 billion overnight.Of course, we don’t tell anyone that our new drug is just a placebo, with no active chemical ingredients. How many patients who take Placebin will recover?

Numerous research studies have shown that if you give an inert placebo to people who are suffering from depression, at least 30% to 40% of them will recover. This means that in a few weeks, 300,000 to 400,000 of the patients in our clinical trial will recover. They’ll swear by the drug and tell their friends how great it is. Some may even appear on Oprah[/] and provide glowing testimonials about how Placebin corrected the chemical imbalance in their brains and changed their lives. The airwaves will be flooded with ads for the remarkable new medication, and hundreds of thousands of people will rush to their doctors to get prescriptions for it. Controversial books will appear, asking whether it’s ethical to prescribe such powerful “happiness pills.”

But, of course, Placebin didn’t really do anything for anyone. It was the patient’s expectations, not the pills, that caused them to get better. The patients actually healed themselves but didn’t realize it. Hope is the most potent antidepressant in existence.

The placebo effect creates tremendous confusion about how and why medications and psychotherapy work. You can create any kind of kooky new treatment for depression or anxiety, and if yo can convince people that it works, it will be effective for some patients, even if it involves blatant quackery. As a result, you may conclude that your treatment has potent antidepressant or anti-anxiety effects when it doesn’t. This type of deception has been going on for thousands of years. In the old days, snake-oil salesman capitalized on the placebo effect when they sold their magical elixirs. They also capitalized on people’s demands for quick and easy miracle cures for whatever ailed them.

Now, you may be thinking, “Well, this all rather academic, because we know that the antidepressants do work. They’ve been validated in numerous scientific studies and approved by the Food and Drug Administration (FDA).” In fact, the situation isn’t nearly as clear-cut as you might think. Recent studies suggest that all of the currently prescribed antidepressants may have few, if any, real therapeutic effects. For example, in a recent multiuniversity study funded by the National Institute of Mental Health, 320 patients with major depression were randomly assigned to treatment with the herb St. John’s wort, sertraline (Zoloft), or a placebo. The investigators wanted to find out, for once and for all, whether St. John’s wort had any antidepressant effects, so they compared it to a “real” antidepressant on on one hand and an inactive placebo on the other.

Neither the Zoloft nor the St. John’s wort fared very well. Although 32% of the patients who received the placebo recovered, only 25% of the patients who received Zoloft and 24% of the patients who received St JOhn’s wort recovered (2 ) This study clearly showed that St. John’s wort had no antidepressant effects above and beyond its placebo effects. I suspect the poor results with St. John’s wort were widely publicized because the pharmaceutical industry wanted people to stop taking it and start taking antidepressants instead. However, the drug companies didn’t publicize the fact that the antidepressant didn’t fair any better than the St. John’s wort. Neither the Zoloft nor the St. John’s wort had any real antidepressant effects above and beyond their modest placebo effects!

That was one of the best studies on antidepressants ever conducted, and the results were not consistent with the widely held notion that the chemicals called antidepressants actually have strong and specific antidepressant effects. Were these results just an aberration of some type? In their review of the world literature, as well as all the data that’s been submitted to the...FDA...by drug companies over the past several decades, Dr. Irving Kirsch, from the University of Connecticut, and his colleagues have concluded that these results are actually very typical. Their analyses indicate that the differences between antidepressants and placebos are minimal at best and that at least 75% to 80% of the effects we attribute to antidepressants medications result from their placebo effects (3a, 3b).

[T]he problem...[is that]...the types of data the drug companies have submitted to the FDA to gain approval for their new antidepressants. In these studies, thousands of patients with moderate to severe depression were randomly assigned to treatment with a placebo or antidepressant (4). Their scores on the Hamilton Rating Scale for Depression averaged 25. The higher the score on the...Scale..., the worse the depression.... [A] 25-point reduction in scores would be needed for a full recovery. The patients who received the antidepressant experienced a 1-point reduction in their depression scores; those who received a placebo experienced an 8-point reduction.

There are three striking things about these results. FIrst, neither the antidepresssants nor the placebo was especially effective. This is particularly disconcerting when you consider the fact that these are the kind of results you’ll find in the [i]most favorable studies that drug companies have conducted.

Second, the difference between the drug and placebo groups was only 2 points. This is the most improvement you could attribute to the the drug itself, and it’s extremely small, especially considering the fact that a 25-point reduction would be needed for full recovery. Some researchers have suggested that such a tiny effect probably does not justify prescribing antidepressants, given the significant side effects, toxic effects, and hazards associated with these agents (5a, 5b, 5c).

Finally, 8 of the 10 points of improvement in the drug group, or 80%, clearly resulted from the placebo effect, not from the drug itself. I want to be clear crystal clear about what this means, because it’s important, and it may seem confusing if you’re not used to thinking about research studies. If you’re feeling depressed and I give you a placebo, but I tell you that you’re receiving a real antidepressant, you’ll experience an 8-point improvement in depression, on average. If, instead, I give you a “real” antidepressant like Prozac, you’ll experience a 10-point improvement in depression, on average. This means that 80% of the improvement you experience when I give you Prozac will actually result from the placebo effect, not from the Prozac. In other words, when people believe that they’ve responded to an antidepressant, in most cases, their improvement actually resulted from the placebo effect, not from any real effects of the drgu itself.

Keep in mind [these are] the best studies that drug companies have published, and it’s not very encouraging. However, drug companies suppress the results of many studies that don’t come out in the “right” way.... Industry insiders will tell you that studies like this are common, but the results are rarley published--for obvious reasons. The drug companies don’t want you to know about studies with results that are unfavorable to the drugs they’re marketing As a result, there’s a bias in the literature, because the drug companies are extremely selective about what they’ll publish. This leads to false perceptions about the effectiveness of antidepresssants; the published studies nearly always seem to favor the medication over the placebo.

Drug companies use all sorts of tricks to try to stack the deck in their favor. For example, patients who enlist in...a study are told that they’ll be randomly assigned to receive either the new antidepressant or a placebo. They’re not told what group they’re in, and the researchers who assess their moods aren’t told either. This is a called a double-blind study, because neither their patients not doctors knew which group a patient is in. So far, so good. This sounds like good science.

However, patients are also informed that the placebo is totally inert, so if they receive the placebo, it will have absolutely no side effects or effects of any kind. In contrast, they’re told that if they receive the antidepressant, they should expect some side effects.... Once the study begins, patients who experience side effects usually conclude that they’re taking the antidepressants. In contrast, patients who don’t experience any side effects usually conclude they’re in the placebo group. If you ask patients which group they think they’re in, they’ll be correct as often as 80% of the time. And if you ask researchers who monitor their progress, their guess usually will be correct, too.

This means that the studies aren’t really double blind, because both patients and researchers know very well who’s receiving the antidepressants and who’s receiving the placebo. Patients with side effects generally conclude that they’re getting the powerful new antidepressant, so they become more hopeful and optimistic. As a result, the depression scores may improve. In contrast, patients who think they’re getting the placebo may feel discouraged because they tell themselves, “Darn it! I ended up in the placebo group. A placebo can’t help me. This always happens to me!” As a result, their depression scores may worsen. This can create an artificial but statistically significant difference between the drug and the placebo groups, even when no real difference exists.

These studies have many other serious flaws, as well, flaws that are particularly egregious because they are easily solvable. For example, the drug companies could use active placebos rather than inactive placebos. If the drug they’re testing caused sedation, they could use an antihistamine like Benadryl for the placebo, because this medication makes you feel sleepy. Or if the drug they’re testing causes feelings of speediness, nervousness, and diarrhea, like Prozac, they could use caffeine for the placebo. That way, the patients would have a much harder time figuring out what group they’re in.

Why don’t the drug companies correct these flaws in their research methods? This is a case where the needs of marketing clash with the needs of science. If a drug company can come up with two studies that demonstrate a statistically significant difference between their new drug and a placebo, they’ll receive FDA approval to market the drug. The value of their stock will instantly escalate, so there’s a huge financial incentive to make these studies come out in the “proper” way.

Recent studies of antidepressants have been even more troubling. The fact that all of the new antidepressants seem to cause significant increase in the rates of completed suicide in children has been well publicized. The FDA recently has required so-called black box warnings for these drugs--labels reserved for the most dangerous drugs (6a, 6b, 6c). BUT YOU MAY NOT HAVE HEARD THAT THE SAME LINK BETWEEN ANTIDEPRESSANT USE AND SUICIDE EXISTS WITH ADULTS.

Dr. David Healy, from the University of Wales College of Medicine, recently used the Freedom of Information Act to obtain all the data in the FDA on adults who were randomly assigned to SSRI antidepressants..., or placebos, in worldwide drug company studies. He discovered that the suicide rates in the patients who received antidepressants were nearly three times higher than the rates in patients who received placebos 7 If these drugs really had antidepressant effects, why would they cause such striking increases in suicide rates in both children and adults? You could even argue that antidepressants shouldn’t be prescribed for anyone who’d feeling depressed!

These studies suggest that true antidepressant medications may not yet exist. Chemicals like Prozac and Paxil are called antidepressants, but their true antidepressant effects are underwhelming at best. Many people find these studies hard to swallow at first. We all know someone who’s said, “Prozac really worked for me. It saved my life.” But remember that at least 30% to 40% of the people who receive a placebo will say exactly the same thing.

My clinical experience over the years has been consistent with new research.... I started out doing brain research and psychopharmacology at the Affective Disease Research Unit at the University of Pennsylvania School of Medicine. During that time, I gave out antidepressants by the bucketful. A few of my patients were helped a lot, and some were helped a little, but many weren’t helped at all. These experiences were sharply at odds with what I heard when I attended the annual American Psychiatric Association conventions or continuing education symposia sponsored by drug companies. I kept hearing that 80% of depressed or anxious patients could be treated successfully with antidepressants, and I couldn’t understand why clinical experiences were so greatly at odds with the party line. I knew that I wasn’t doing a poor job prescribing the medications. We had one of the finest psychopharmacology teams in the world....

Over the years, I’ve had more than 35,000 psychotherapy sessions with depressed and anxious patients, and I’m every bit as enthusiastic about Cognitive Behavioral Therapy as when I first began learning about it (pp. 53-61 & 412-413, 1st Ed.).

Dr. Burns’ other credentials include:

Dr. Burns graduated magna cum laude from Amherst College, received his M.D. from Stanford University School of Medicine and completed his psychiatry residency at the University of Pennsylvania School of Medicine. He has served as Acting Chief of Psychiatry at the Presbyterian / University of Pennsylvania Medical Center (1988) and Visiting Scholar at the Harvard Medical School (1998) and is certified by the National Board of Psychiatry and Neurology.

Dr. Burns is currently Adjunct Clinical Professor Emeritus of Psychiatry and Behavioral Sciences at the Stanford University School of Medicine, where he is involved in research and teaching. He has received numerous awards, including the A. E. Bennett Award for his research on brain chemistry, the Distinguished Contribution to Psychology through the Media Award, and the Outstanding Contributions Award from the National Association of Cognitive-Behavioral Therapists. He has been named Teacher of the Year three times from the class of graduating residents at Stanford University School of Medicine, and feels especially proud of this award.

In addition to his academic research, Dr. Burns has written a number of popular books on mood and relationship problems. His best-selling book, Feeling Good: The New Mood Therapy, has sold over 4 million copies in the United States, and many more worldwide. Feeling Good is the book most frequently "prescribed" for depressed patients by psychiatrists and psychologists in the United States and Canada. Surveys indicate that American mental health professionals rate Feeling Good as the #1 book on depression, out of a list of 1,000 self-help books.

In 1995, Dr. Burns and his family returned to California. When he is not crunching statistics for his research at Stanford, he can be found giving workshops for mental health professionals throughout the United States and Canada.

Danielion wrote:According to this JAMA meta-analysis, anti-depressants are no better than placebos.

JAMA wrote:For patients with very severe depression, the benefit of medications over placebo is substantial

Funny, that.

“No lists of things to be done. The day providential to itself. The hour. There is no later. This is later. All things of grace and beauty such that one holds them to one's heart have a common provenance in pain. Their birth in grief and ashes.” - Cormac McCarthy, The Road

Learn this from the waters:in mountain clefts and chasms,loud gush the streamlets,but great rivers flow silently.- Sutta Nipata 3.725

Danielion wrote:According to this JAMA meta-analysis, anti-depressants are no better than placebos.

JAMA wrote:For patients with very severe depression, the benefit of medications over placebo is substantial

Funny, that.

Not including that sentence would've been disingenuous on my part. In the context of all the studies I cited, however, it has no impact on the general demonstration that antidepressants only work on a statistically insignificant fraction of depressed individuals, and that the risks usually far outweigh the benefits (as the the excerpt from Dr. Burns shows).

One possible answer: There are many different kinds of anti-depressants. Maybe some ADs work better than others. Unfortunately there is no one-size-fits all.

But generally, I am not much in favor of current types of ADs.

"Life is a struggle. Life will throw curveballs at you, it will humble you, it will attempt to break you down. And just when you think things are starting to look up, life will smack you back down with ruthless indifference..."

Alex123 wrote:One possible answer: There are many different kinds of anti-depressants. Maybe some ADs work better than others. Unfortunately there is no one-size-fits all.

But generally, I am not much in favor of current types of ADs.

Dr. Burns will prescribe occasionally. I don't want to make it sound like he's engaging in what he calls All-Or-Nothing-Thinking. In his book on depression, (Feeling Good) he devotes several chapters to ADs, including a guide to choosing the right one for you if you and a professional decide it would be best.

However, ADs never work all by themselves. If that were the case, we'd all be on them. Placebos are just one among many confounded variables.

danieLion wrote:However, ADs never work all by themselves. If that were the case, we'd all be on them. Placebos are just one among many confounded variables.

Maybe life really is beautiful when one takes the right anti-depressant?

"Life is a struggle. Life will throw curveballs at you, it will humble you, it will attempt to break you down. And just when you think things are starting to look up, life will smack you back down with ruthless indifference..."